Studies utilizing a variety of experimental approaches have established the existence of an inhibitory nervous system in mammalian airways which is neither adrenergic nor cholinergic. As the neurotransmitter has not been identified, the system commonly is referred to as the nonadrenergic noncholinergic inhibitory system (NANCIS). The functional significance of this nervous system and its role in the pathophysiology of human airways disease are slowly being uncovered. A role for inflammation in the genesis of human airway hyperactivity also is emerging. However, the influence of the inflammatory process on the airway NANCIS is unknown. Also unknown is the identity of the chemical transmitter utilized by the system for postganglionic transmission. In addition, little is known about the system's basic pharmacological characteristics, save that it is insensitive to a variety of pharmacological antagonists enzymatic interventions. Previous studies in our laboratory have established the functional significance of the NANCIS in the intact cat. Experiments performed in vitro have since confined and extended these findings. The studies outlined in the current proposal will utilize in vivo, in situ, in vitro and analytical techniques to: (I) demonstrate release and determine the nature of the NANCIS chemical transmitter in airways; and (2) examine the role of the airway NANCIS in airway inflammatory disease by assessing whether inflammation per se influences NANCIS function and whether NANCIS activation plays a role in regulating the release of inflammatory mediators and the progression of airways inflammation. It is envisaged that elucidation of the interactions between the NANCIS and airway inflammation will provide new insights into the means by which inflammation is associated with airway hyperactivity. Further, identification of the NANCIS neurotransmitter will provide a foundation for the development of more effective therapeutic agents for the treatment of hyperactive airways disease.